Colon cancer is initiated by stem cells that escape the strict control. This process is often driven through aberrant activation of Wnt signaling by mutations in components acting downstream of the receptor complex that unfetter tumor cells from the need for Wnts. Here we describe a class of colon cancer that does not depend on mutated core components of the Wnt pathway. Genetically blocking Wnt secretion from epithelial cells of such tumors results in apoptosis, reduced expression of colon cancer markers, followed by enhanced tumor differentiation. In contrast to the normal colonic epithelium, such tumor cells autosecrete Wnts to maintain their uncontrolled proliferative behavior. In humans, we determined certain cases of colon cancers in which the Wnt pathway is hyperactive, but not through mutations in its core components. Our findings illuminate the path in therapy to find further subtypes of Wnt-dependent colon cancer that might be responsive to Wnt secretion inhibitors.

Department of Biosystems Science and Engineering ETH Zürich Basel Switzerland

Department of Molecular Biology and Genetics Bilkent University Ankara Turkey

Department of Molecular Life Sciences University of Zurich Winterthurerstrasse 190 CH 8057 Zurich Switzerland

Department of Pathology and Molecular Pathology University Hospital Zurich Zurich Switzerland

Graduate School of Informatics Department of Health Informatics METU Ankara Turkey

Institute of Molecular Genetics of the ASCR v v i Vídeňská 1083142 20 Prague 4 Czech Republic

National Nanotechnology Center Bilkent University Ankara Turkey

Swiss Institute for Experimental Cancer Research School of Life Sciences 1015 Lausanne Switzerland

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